Dosage compensation can buffer copy-number variation in wild yeast
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE61532 | GEO | 2015/05/08
SECONDARY ACCESSION(S): PRJNA261399
REPOSITORIES: GEO
Similar Datasets
Project description:We show that aneuploidy is common in wild isolates of yeast, which are inherently tolerant to chromosome amplification and down-regulate expression at 40% of amplified genes. To dissect the mechanism of this dosage response, we generated isogenic strain panels in which diploid cells carried either two, three, or four copies of the affected chromosomes. Using a mixture of linear regression (MLR) model to classify genes, we find that expression is actively down regulated in proportion to increased gene copy at up to 30% of genes. Genes subject to dosage control are under higher expression constraint – but show elevated rates of gene amplification – in wild populations, suggesting that dosage compensation buffers copy number variation (CNV) at toxic genes RNA-seq and transcriptome analysis of S. cerevisiae natural isolates having aneuploidy. Technical triplicate was performed for isogenic diploid strains having 2, 3 and 4 copies of a given chromosome (strain panels), while technical duplicate or singulate was performed on all other aneuploids.
2015-05-08 | E-GEOD-61532 | biostudies-arrayexpress
Project description:Copy-number variants (CNVs) are large-scale amplifications or deletions of DNA that can drive rapid adaptive evolution and result in large-scale changes in gene expression. Whereas alterations in the copy number of one or more genes within a CNV can confer a selective advantage, other genes within a CNV can decrease fitness when their dosage is changed. Dosage compensation - in which the gene expression output from multiple gene copies is less than expected - is one means by which an organism can mitigate the fitness costs of deleterious gene amplification. Previous research has shown evidence for dosage compensation at both the transcriptional level and at the level of protein expression; however, the extent of compensation differs substantially between genes, strains, and studies. Here, we investigated sources of dosage compensation at multiple levels of gene expression regulation by defining the transcriptome, translatome and proteome of experimentally evolved yeast (Saccharomyces cerevisiae) strains containing adaptive CNVs.
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Project description:DNA copy number alterations play an important role in cancer development and progression by changing the transcriptional levels of key cancer-related genes. However, gene expression patterns may also be affected by other mechanisms. To test these basic principles, we have applied genome-wide screening techniques to 53 invasive breast tumors with array comparative genomic hybridization and gene expression microarrays to assess the direct effect of gene dosage on gene expression levels and independently to test the effect of other mechanisms on transcriptional levels. Low-level gain, high-level gain/amplification, heterozygous loss and homozygous deletion (henceforth referred to as gain, amplification, loss and deletion) were defined as log2 ratio thresholds set at +0.2, ≥+0.5, -0.2 and ≤-1.0, respectively.
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Project description:Genomic loci associated with common traits and diseases are typically non-coding and likely impact gene expression, sometimes coinciding with rare loss-of-function variants in the target gene. However, our understanding of how gradual changes in gene dosage affect molecular, cellular, and organismal traits is currently limited. To address this gap, we induced gradual changes in gene expression of four genes using CRISPR activation and inactivation. Downstream transcriptional consequences of dosage modulation of three master trans-regulators associated with blood cell traits (GFI1B, NFE2, and MYB) was examined using targeted single-cell multimodal sequencing. We showed that guide tiling around the TSS is the most effective way to modulate cis gene expression across a wide range of fold-changes, with further effects from chromatin accessibility and histone marks that differ between the inhibition and activation systems. Our single-cell data allowed us to precisely detect subtle to large gene expression changes in dozens of trans genes, revealing that many responses to dosage changes of these three TFs are non-linear, including non-monotonic behaviours, even when constraining the fold-changes of the master regulators to a copy number gain or loss. We found that the dosage properties are linked to gene constraint and that some of these non-linear responses are enriched for disease and GWAS genes. Overall, our study provides a straightforward and scalable method to precisely modulate gene expression and gain insights into its downstream consequences at high resolution.
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Project description:Copy-number variants (CNVs) are large-scale amplifications or deletions of DNA that can drive rapid adaptive evolution and result in large-scale changes in gene expression. Whereas alterations in the copy number of one or more genes within a CNV can confer a selective advantage, other genes within a CNV can decrease fitness when their dosage is changed. Dosage compensation - in which the gene expression output from multiple gene copies is less than expected - is one means by which an organism can mitigate the fitness costs of deleterious gene amplification. Previous research has shown evidence for dosage compensation at both the transcriptional level and at the level of protein expression; however, the extent of compensation differs substantially between genes, strains, and studies. Here, we investigated sources of dosage compensation at multiple levels of gene expression regulation by defining the transcriptome, translatome and proteome of experimentally evolved yeast (Saccharomyces cerevisiae) strains containing adaptive CNVs. We quantified the gene expression output at each step and found evidence of widespread dosage compensation at the protein abundance (~47%) level. By contrast we find only limited evidence for dosage compensation at the transcriptional (~8%) and translational (~3%) level. We also find substantial divergence in the expression of unamplified genes in evolved strains that could be due to either the presence of a CNV or adaptation to the environment. Detailed analysis of 82 amplified and 411 unamplified genes with significantly discrepant relationships between RNA and protein abundances identified enrichment for upstream open reading frames (uORFs). These uORFs are enriched for binding site motifs for SSD1, an RNA binding protein that has previously been associated with tolerance of aneuploidy. Our findings suggest that, in the presence of CNVs, SSD1 may act to alter the expression of specific genes by potentiating uORF mediated translational regulation.
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Project description:Copy-number variants (CNVs) are large-scale amplifications or deletions of DNA that can drive rapid adaptive evolution and result in large-scale changes in gene expression. Whereas alterations in the copy number of one or more genes within a CNV can confer a selective advantage, other genes within a CNV can decrease fitness when their dosage is changed. Dosage compensation - in which the gene expression output from multiple gene copies is less than expected - is one means by which an organism can mitigate the fitness costs of deleterious gene amplification. Previous research has shown evidence for dosage compensation at both the transcriptional level and at the level of protein expression; however, the extent of compensation differs substantially between genes, strains, and studies. Here, we investigated sources of dosage compensation at multiple levels of gene expression regulation by defining the transcriptome, translatome and proteome of experimentally evolved yeast (Saccharomyces cerevisiae) strains containing adaptive CNVs. We quantified the gene expression output at each step and found evidence of widespread dosage compensation at the protein abundance (~47%) level. By contrast we find only limited evidence for dosage compensation at the transcriptional (~8%) and translational (~3%) level. We also find substantial divergence in the expression of unamplified genes in evolved strains that could be due to either the presence of a CNV or adaptation to the environment. Detailed analysis of 82 amplified and 411 unamplified genes with significantly discrepant relationships between RNA and protein abundances identified enrichment for upstream open reading frames (uORFs). These uORFs are enriched for binding site motifs for SSD1, an RNA binding protein that has previously been associated with tolerance of aneuploidy. Our findings suggest that, in the presence of CNVs, SSD1 may act to alter the expression of specific genes by potentiating uORF mediated translational regulation.
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Project description:Genetic variation that underlies phenotypic differences provides the material on which evolutionary selection acts. Gene duplication/amplification is one type of genetic variation that can allow an organism to rapidly respond to environmental changes by increasing gene dosage. While the potential benefits afforded by gene amplification during evolution are well known, there is also a significant fitness cost to increasing gene dosage including resource shortages and burdening cellular systems. Although the evolutionary importance of gene duplication has long been appreciated, little is known about natural variation in the tolerance of duplication of specific genes. To investigate this question, we expressed the same high-copy gene overexpression (OE) library in a laboratory strain and 14 different wild S. cerevisiae isolates, together representing 4 lineages and several admixed strains, to explore the natural variation in tolerance to gene OE. Our results distinguish universal effects common to many studied strains versus strain-specific effects including broad-scale and gene-specific differences in the consequences of OE. These results raise important implications for the accessibility of evolutionary trajectories afforded by gene OE, depending on genetic background.
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Project description:Post-Translational Dosage Compensation Buffers Genetic Perturbations to Stoichiometry of Protein Complexes
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Project description:This a model from the article:
Increased glycolytic flux as an outcome of whole-genome duplication in yeast.
Conant GC, Wolfe KH Mol. Syst. Biol.
[2007 ; Volume: 3 (Issue: )]: 129 17667951
,
Abstract:
After whole-genome duplication (WGD), deletions return most loci to single copy. However, duplicate loci may survive through selection for increased dosage. Here, we show how the WGD increased copy number of some glycolytic genes could have conferred an almost immediate selective advantage to an ancestor of Saccharomyces cerevisiae, providing a rationale for the success of the WGD. We propose that the loss of other redundant genes throughout the genome resulted in incremental dosage increases for the surviving duplicated glycolytic genes. This increase gave post-WGD yeasts a growth advantage through rapid glucose fermentation; one of this lineage's many adaptations to glucose-rich environments. Our hypothesis is supported by data from enzyme kinetics and comparative genomics. Because changes in gene dosage follow directly from post-WGD deletions, dosage selection can confer an almost instantaneous benefit after WGD, unlike neofunctionalization or subfunctionalization, which require specific mutations. We also show theoretically that increased fermentative capacity is of greatest advantage when glucose resources are both large and dense, an observation potentially related to the appearance of angiosperms around the time of WGD.
The original model submitted by the authors was slightly altered and now comprises the models originally submitted as MODEL2426780967, MODEL2427021978, MODEL2427095802. It reproduces figures 2A,3A and 3B from the publication.
This model uses the glycolysis model from Pritchard and Kell (2002) with an additional parameter, WGD_E
, to adjust for the differing enzyme conzentrations before the whole genome duplication (WGD) and parameters fV_xxx
that adjust the Vmax
of the different reactions (xxx eg. HXT or PYK).
Figure 3A from the article can be reproduced by changing the value of the parameters fV_xxx
to 0.9 indiviually, with xxx signifying the different enzymes (HXT, HXK ...)
Figure 3B from the publication can be reproduced by setting the parameter WGD_E
to 0.75 and individually setting the parameters fV_xxx
to 1.333.
To reproduce figure 2A from the article change the parameter WGD_E
in the range between 0.65 and 1.0.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team.
For more information see the terms of use
.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000176 | BioModels